Novel approaches to monitoring and utilizing adherence to HIV therapy in Africa In this competitive renewal, we propose to use a novel method of real-time wireless adherence monitoring in one of the best established multi-disciplinary HIV antiretroviral treatment cohorts in rural Africa. We will advance our theoretical understanding of HIV antiretroviral adherence behavior, HIV pathogenesis, and we will potentially solve some of the most vexing problems in resource-limited settings, namely the monitoring and prevention of HIV antiretroviral treatment failure. Based on a successful pilot study in rural Uganda and favorable cost-effective estimates, we will deploy the Wisepill real-time wireless adherence monitoring system to objectively monitor adherence in real time. We will determine to what extent social capital mitigates economic barriers to long-term adherence and determine if the pervasive impact of stigma on adherence operates through social capital (Aim 1). We will determine the relationship between missed doses, low-level viremia (between 1 and 50 copies RNA/mL), inflammation, bacterial translocation, suboptimal CD4 response, and mortality (Aim 2). Finally, we will investigate the relationship between complex adherence patterns and viral failure to both inform selective viral load monitoring and to lay the foundation for the first-of-kind intervention to prevent viral failure after missed doses, but before viral rebound (Aim 3). We will secure behavioral and biologic data over nine years of potential treatment by recruiting 500 additional people to our existing cohort in Mbarara, Uganda for a total of 775 participants. This study will continue our 15-year track record of new discoveries in the intersection between HIV treatment adherence behavior and pathogenesis. This research program has launched careers of over 50 domestic and 15 Uganda junior investigators and has generated over 250 publications, including 64 publications in leading journals during the current funding cycle. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Novel approaches to monitoring and utilizing adherence to HIV therapy in Africa Real-time wireless adherence monitoring deployed by leading investigators in the biology and behavior of HIV has the potential to generate new insights into antiretroviral adherence behavior, HIV pathogenesis, and therapeutic monitoring. The extent to which we find wireless adherence monitoring effective at detecting impending treatment failure will provide a strong rationale and framework for studies to prevent treatment failure in the US where resources for interventions and costs associated with treatment failure are several times greater. Thus, this study has the potential to transform HIV practice in both resource-limited and resource-rich settings, including the US. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page